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Prime Editing: An Overview.
CRISPR tools are revolutionizing the landscape of genetic therapies, with the potential to cure a range of previously untreatable diseases. Among all the available genome editing technologies, prime editing is an especially versatile tool that enables precise genetic modifications, including point mutations, insertions, and deletions, without inducing double-strand breaks or requiring a donor DNA template. Through structural modifications and the development of novel systems with additional functionalities, prime editing has expanded its applicability with improved precision, efficacy, and safety. It is already being tested in clinical trials for chronic granulomatous disease, and many preclinical studies are underway. However, significant challenges remain for its broad applicability as a potential curative therapy for human genetic diseases, mainly related to ensuring efficient and safe delivery to target tissues.
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Cell-Penetrating Peptide Delivery for CRISPR Applications.
Cell-penetrating peptides (CPPs) provide a modular nonviral strategy for intracellular delivery of CRISPR/Cas9 components, particularly preassembled Cas9 ribonucleoprotein (RNP) complexes. This chapter summarizes key principles of CPP-mediated Cas9 RNP delivery, including noncovalent complexation and covalent CPP-Cas9 conjugation strategies. A representative protocol is provided for the preparation and evaluation of Cas9-K5 RNP, including in vitro uptake and reporter-editing assays, nucleofection-based functional controls, local intracranial delivery, immunofluorescence staining, and quantitative analysis of reporter activation in brain tissue.
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A carrier-free multiplexed gene editing system applicable for suspension cells.
Genetically engineered cells via CRISPR/Cas9 system can serve as powerful sources for cancer immunotherapeutic applications. Furthermore, multiple genetic alterations are necessary to overcome tumor-induced immune-suppressive mechanisms. However, one of the major obstacles is the technical difficulty with efficient multiple gene manipulation of suspension cells due to the low transfection efficacy. Herein, we established a carrier-free multiplexed gene editing platform in a simplified method, which can enhance the function of cytotoxic CD8+ T cells by modulating suspension cancer cells. Our multiple Cas9 ribonucleoproteins (RNPs) enable simultaneous disruption of two programmed cell death 1 (PD-1) ligands, functioning as negative regulators in the immune system, by accessing engineered Cas9 proteins with abilities of complexation and cellular penetration. In addition, combination with electroporation enhanced multiple gene editing efficacy, compared with that by treatment of multiple Cas9 RNPs alone. This procedure resulted in high gene editing at multiple loci of suspension cells. The treatment of multiple Cas9 RNPs targeting both ligands strongly improved Th1-type cytokine production of cytotoxic CD8+ T cells, resulting in synergistic cytotoxic effects against cancer. Simultaneous suppression of PD-L1 and PD-L2 on cancer cells via our developed editing system allows effective anti-tumor immunity. Furthermore, the treatment of multiple Cas9 RNPs targeting PD-L1, PD-L2, and TIM-3 had approximately 70-90% deletion efficacy. Thus, our multiplexed gene editing strategy endows potential clinical utilities in cancer immunotherapy.
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High-fidelity, efficient, and reversible labeling of endogenous proteins using CRISPR-based designer exon insertion.
Precise and efficient insertion of large DNA fragments into somatic cells using gene editing technologies to label or modify endogenous proteins remains challenging. Non-specific insertions/deletions (INDELs) resulting from the non-homologous end joining pathway make the process error-prone. Further, the insert is not readily removable. Here, we describe a method called CRISPR-mediated insertion of exon (CRISPIE) that can precisely and reversibly label endogenous proteins using CRISPR/Cas9-based editing. CRISPIE inserts a designer donor module, which consists of an exon encoding the protein sequence flanked by intron sequences, into an intronic location in the target gene. INDELs at the insertion junction will be spliced out, leaving mRNAs nearly error-free. We used CRISPIE to fluorescently label endogenous proteins in mammalian neurons in vivo with previously unachieved efficiency. We demonstrate that this method is broadly applicable, and that the insert can be readily removed later. CRISPIE permits protein sequence insertion with high fidelity, efficiency, and flexibility.
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Towards the elimination of infectious HPV: exploiting CRISPR/Cas innovations.
HPV has been conclusively associated with various human malignancies, making the development of prevention and treatment strategies for HPV-induced diseases a high priority. Currently, primary prevention methods include HPV immunization and routine screening, which significantly reduce the risk of HPV transmission. However, for patients diagnosed with invasive, advanced, or recurrent malignancies, non-virus-specific therapies frequently lead to drug resistance and adverse effects, resulting in minimal improvement in treatment efficacy for numerous patients. Viral genome-targeting therapy is emerging as a promising avenue for the future management of HPV infections. With the rapid advancement of genetic modification technologies, the CRISPR/Cas system has demonstrated significant potential in treating viral infections. Its ability to selectively target and edit viral genomes for elimination positions it as a highly effective approach for combating HPV. This review will explore the functions and applications of the CRISPR/Cas system as an innovative therapy for HPV. We will illustrate the prospective efficacy of CRISPR/Cas as a groundbreaking and promising cure for HPV infections, while also addressing the opportunities and challenges associated with this novel approach.
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Gene Editing to Generate Versatile Human Pluripotent Stem Cell Reporter Lines for Analysis of Differentiation and Lineage Tracing.
Transcription factors (TFs) are potent proteins that control gene expression and can thereby drive cell fate decisions. Fluorescent reporters have been broadly knocked into endogenous TF loci to investigate the biological roles of these factors; however, the sensitivity of such analyses in human pluripotent stem cells (hPSCs) is often compromised by low TF expression levels and/or reporter silencing. Complementarily, we report an inducible and quantitative reporter platform based on the Cre-LoxP recombination system that enables robust, quantifiable, and continuous monitoring of live hPSCs and their progeny to investigate the roles of TFs during human development and disease. Stem Cells 2019;37:1556-1566.
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Application of Gene Editing in Triple-Negative Breast Cancer Research.
With the rapid development of gene editing technology, its application in breast cancer has gradually become the focus of research. This article reviews the application of gene editing technology in the treatment of breast cancer, and discusses its challenges and future development directions. The key application areas of gene editing technology in the treatment of breast cancer will be outlined, including the discovery of new therapeutic targets and the development of drugs related to the pathway. Gene editing technology has played an important role in the discovery of new therapeutic targets. Through the use of gene editing technology, breast cancer-related genes are systematically edited to regulate key regulatory factors on related pathways or key tumor suppressor genes such as FOXC1 and BRCA, and the results are analyzed in cell or animal experiments, and the target is obtained from the experimental results, which provides important clues for the development of new drugs. This approach provides an innovative way to find more effective treatment strategies and inhibit tumor growth. In addition, gene editing technology has also promoted the personalization of breast cancer treatment. By analyzing a patient's genomic information, researchers can pinpoint key genetic mutations in a patient's tumor and design personalized treatments. This personalized treatment approach is expected to improve the therapeutic effect and reduce adverse reactions. Finally, the application of gene editing technology also provides support for the development of breast cancer immunotherapy. By editing immune cells to make them more potent against tumors, researchers are trying to develop more effective immunotherapies to bring new treatment options to breast cancer patients.
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Operationalising a Haemophilia Gene Editing Lexicon for Practical Use.
INTRODUCTION: Gene editing therapies offer the possibility of substantial improvement in treatment and quality of life for people with haemophilia (PWH) in a landscape of dynamic therapeutic advancement. Developing a common and understandable language to discuss gene editing will be essential to ensure these treatments can be deployed in a safe and effective manner with fully informed and shared decision-making between healthcare professionals (HCPs) and PWH. A lexicon explaining and clarifying key concepts is one potential tool to address these aims. Here we evaluate how a gene editing lexicon could be deployed to maximise impact and improve patient outcomes. AIM: To operationalise the gene editing lexicon for successful adoption by the haemophilia community. METHODS: Through an innovative, iterative process, representatives from the haemophilia community, including multidisciplinary HCPs, PWH, and caregivers, with support from language strategy experts, developed a gene editing lexicon and evaluated operational aspects for real-world adoption of this resource. RESULTS: A gene editing lexicon was developed, including infographics illustrating key concepts. Infographics were adapted from the lexicon to further clarify and communicate these concepts. Infographics were found to be a potentially vital tool for enhancing the practical use of the lexicon to promote shared decision-making and attain informed consent for gene editing therapies. CONCLUSION: A gene editing lexicon shows promise for improving the understanding of gene editing for all stakeholders in the haemophilia community. Ensuring the lexicon remains up to date with current therapies and appropriate strategies for adoption such as infographics will enable this resource to have maximum impact.
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InUtero Gene Therapy: Progress and Challenges.
In utero gene therapy has the potential to treat lethal and morbid perinatal diseases before birth. Small fetal size, a tolerogenic immune system, and dosing efficiency make the fetus a compelling patient. Numerous clinical, social, and institutional factors must be considered to achieve the promise of genetic treatment before birth.
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Gene Editing: Practical Application in the Lab.
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